RESUMO
Virus-specific CD8 T cells after clearance of infection reduce their number in lymphoid organs by apoptotic death and by migration into peripheral tissues. During and after infection, many lymphocytic choriomeningitis virus (LCMV)-specific CD8 T cells in lymphoid but not peripheral tissues are in a preapoptotic state, as detected by the early apoptosis marker annexin V. In this report, we investigated the significance of this preapoptotic state and how it may be influenced by viral epitope specificity. Stimulation with anti-CD3 or IL-2 in vitro postponed DNA fragmentation in annexin V+ cells, but adoptive transfer studies in vivo showed that this preapoptotic phenotype precluded the development of functional memory. CD8 T cells specific to LCMV epitopes NP396 and gp33 differed in their preapoptotic state, with NP396-specific T cells binding more annexin V than gp33-specific T cells. These epitope- and tissue-dependent differences were seen in primary, memory, and secondary responses and in mice receiving different displays of Ag by infection with LCMV strains of different tropisms or by infection with vaccinia virus recombinants expressing LCMV proteins. Thus, the epitope-dependent differences in apoptosis were independent of virus tropisms, duration of Ag exposure, and competition within APCs, and were an intrinsic property of the epitope. The tissue-dependent and epitope-dependent preapoptotic state correlated with reduced expression of IL-7Ralpha.
Assuntos
Apoptose , Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T , Memória Imunológica , Vírus da Coriomeningite Linfocítica/imunologia , Animais , Anexina A5/análise , Antígenos Virais/imunologia , Complexo CD3/imunologia , Fragmentação do DNA , Glicoproteínas/imunologia , Imunofenotipagem , Interferon gama/biossíntese , Interleucina-2/farmacologia , Coriomeningite Linfocítica/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Nucleocapsídeo , Nucleoproteínas/imunologia , Especificidade de Órgãos , Fragmentos de Peptídeos/imunologia , Receptores de Interleucina-7/análise , Proteínas do Core Viral/imunologia , Proteínas Virais/imunologiaRESUMO
CD8(+) T-cell memory to viruses is stable in the absence but volatile in the presence of other infections. Apoptotic events that occur early in acute infections delete pre-existing memory T cells, leaving the host with reduced memory (except for cross-reactive responses) to previously encountered viruses. Apoptotic events also silence the acute immune response, leaving the host with a residual population of memory T cells. Persistent infections can induce apoptotic deletions of memory T cells that are specific to the persisting virus and to previously encountered pathogens.